Production of alpha-nitroesters



PRODUCTION OF OL'NITROESTERS Robert K. Blackwood, Uncasville, Conn., andNathan Kornblum, West Lafayette, Ind., assignors to Purdue ResearchFoundation, Lafayette, Ind., a corporation of Indiana ApplicationFebruary 28, 1956, Serial No. 568,183

3 Claims. (Cl. 260--471) The present invention relates to thepreparation of nitroesters wherein the nitro group, -Nz is positionedalpha to the carbalkoxyl radical. More particularly, the presentinvention pertains to the preparation of such nitro compounds, commonlycalled alpha-n-itroesters, from the corresponding alpha-haloesters.

In U. S. patent application 505,560, filed May 2, 1955 in the name ofNathan Kornblum, there is disclosed a method for the preparation ofnitroalkanes which comprises reacting an alkali metal nitrite indimethylformamide with an ester of a cycloalkanol or a primary orsecondary alkanol and an acid selected from the group consisting ofhydrobromic, hydroiodic, and sulfonic acids. While this process is quitesatisfactory for the preparation of nitroalkanes and nitrocycloalk-anes,as set forth in the said application, it is unsuitable for the synthesisof alpha-nitroesters. When the technique of this process is applied toalpha-haloesters for the pro duction of alpha-nitroesters, both theisomeric nitro and nitrite esters are formed and the joint action of thealkali metal nitrite and the nitrite ester destroys the alpha-nitroesteras it is formed. The products obtained from such a reaction mixture areprimarily the alphahydroxy and alpha-oximino esters.

We have found that pure alpha-nitroesters in relatively high yields maybe obtained by carrying out the react-ion of the alkali metal nitriteand alpha-haloestel's in dimethylformamide in the presence of'a compoundselected from the class consisting of phloroglucinol, resorcinol, andcatechol. The latter compounds act as a scavenger for the nitrite estersand by reacting with any nitrite ester immediately upon its formation,they prevent nitrosation of the alpha-nitroester. Of the threescavengers, phloroglueinol is by far the most efiicient and isdistinctly superior.

A more complete understanding of the invention will be gained from aconsideration of the following examples:

Example 1.Preparati0n of ethyl alpha-nitrobutyrate Ethylalpha-bromobutyrate (58.5 g., 0.30 mole) is poured into a stirredmixture of 600 ml. N,'N-dimethylformamide (DMF), 36 g. of sodium nitrite(0.52 mole) and 40 g. of anhydrous phloroglucinol (0.32 mole) in a 1liter three necked flask equipped with a sealed stirrer. The flask isstoppered, immersed in a water bath maintained at room temperature, andstirring is continued for 2.5 hours. The reaction mixture is then pouredinto 1.2 liter of ice-water layer over with 300 ml. of diethyl ether.After separation of the upper layer, the aqueous phase is extracted fourmore times with 100 ml. portions of ether. The combined extracts arewashed with four 100 ml. portions of water and then dried over anhydrousmagnesium sulfate. The mixture is filtered with suction, the magnesiumsulfate is washed with four 25 ml. portions of ether and these arecombined with the filtrate.

Using a small column, the ether is removed under renited States Patent 2duced pressure, heat being supplied by a bath Whose temperature isgradually raised to ca. 60". The residual yellow liquid is transferred,with the aid of a little anhydrous ether, to a ml. flask, the column isattached and the remaining solvent is removed under reduced pressure.Rectification of theresidue yields 2-3 g. of forerun which comes over inthe range 3371/ 1 min. which is followed by 34-36 g. (70-75%) ofcolorless ethyl alpha-nitrobu-tyra-te (B. P. 71 1 mm.; n 1.4233).

Example 2.Preparati0n of ethyl alpha-hitr0-alphaphenylacetate Theequipment and conditions were similar to those used in Example 1. Thereagents were 300 ml. DM=F, 18 g. NaNOz, 20 g. anhydrous phloroglucinoland 36.5 g. (0.15 mole) ethyl alpha-bromo-alpha-phenlyacetate. Thereaction time was 2.5 hr. After stripping off the ether, the residue wasshaken for 10 min. with a solution of 40 g. NazCOs in 200 ml. of water.The two phase system was extracted with ether and the ether layerdiscarded. The aqueous layer was then acidified with 20% acetic acid.The organic layer which formed was separated and combined with etherextracts of the aqueous layer.- The ether solution was washed withwater, the ether was stripped off and the product was distilled to give51-70% yield of material of constant boiling point (92/0.15 mm.) andrefractive index (11 1.5098).

Example 3.-Preparalion 0 ethyl alpha-nitropropionate The equipment andconditions were similar to those used in Example 1. The reagents usedwere 600 ml. DM-F, 36 g. (0.52 mole) sodium nitrite, 54.3 g. (0.30 mole)ethyl alpha-bromopropionate and 25 g. (0.15 mole) phloroglucinoldihydrate. The reaction time was 5 hr. The deeply brown reaction mixturewas worked up as in Example 1. A 64% yield of ethylalpha-nitropropi-onate, B. P. 54/2 mm.; 11 1.4210 was obtained.

Example 4.Preparatz'0n of ethyl alpha-nitropropionate The equipment andconditions were similar to those used in Example l. The reagents were600 ml. DM'F, 25 g. phloroglucinol (ii-hydrate, 36 g. sodium nitrite and68.4 g. ethyl alphaiodopropionate. Reaction time was 2 hr. at roomtemperature. Rectification gave a 62% yield of the alpha-uitroester; B.P. 50/0.8 mm.; n 1.4210.

Example 5.'Preparati0n of ethyl aIplm-m'troz'sob[My/ate The equipmentand conditions were similar to those used in Example 1. The reagentswere 600 ml. DMF, 36 g. NaNOz and 58.5 g. or" ethylalpha-bromoisobutyrate. Reaction time was 44 hr. Rectification gave a77% yield of ethyl alpha-nitroisobutyrate; B. F. 48/ 1 mm; a 1.4199.

Example 6.-Attempted preparation of ethyl alphaniz'ropropionaze fromethyl alpha-iozlopropionute The equipment and conditions were similar tothose used in Example 4. The reagents were 600 ml. DMF, 36 g. sodiumnitrite, 68.4 g. ethyl alpha-iodopropionate and 40 g. urea. Reactiontime was 6 hr. at 20 to 15. The reaction mixture was Worked up as inExample 4. Rectification gave 3.48 g. (8% yield) of ethylalphanitropropionate, n 14208-14214; B. P. 5052 at 2 mm. In addition 7.2g. of ethyl alpha-oximinopropionate, M. P. and mixed M. P. 94-94.5, wasisolated.

Example 7.Attempted preparation of ethyl alpha-nitr0 propionate fromethyl alpha-bromopropionate The equipment and conditions were similar tothose used in Example 3. The reagents employed were 600 ml. DMF, 35 g.sodium nitrite, 40 g. urea and 54.3 g. (0.3 mole) of ethylalpha-bromopropionate. Reaction time was 3 hr. at room temperature. Onworking up the reaction mixture as in Example 3 pureethylalphaoxinn'noproportionate (M. P. 94-95,.5, mixed M. P. with anauthentic sample 94-94.5) was isolated but none of the desired ethylalpha-nitropropionate was obtained.

An identical experiment, except that a reaction time of 5.5 hours wasused, again gave no ethyl alpha-nitropropionate. Instead a 24% yield ofpure ethyl alpha-oximinopropionate was obtained.

Example 8.-Preparatin of ethyl alpha-nitropropionate The equipment andconditions were similar to those used in Example 7. The reagents were600 ml. DMF, 36 g. sodium nitrite, 54.3 g. ethyl alpha-bromopropionate,40 g. urea and 16.5 g. of resorcinol. Reaction time 3 hr. Thereactionmixture was worked up as in Example 3. A 26% yield of ethylalpha-nitropropionate, B. P. 44 at 0.5 mm.; n 1.4210 was obtained.

In the present process, any alkali metal nitrite is suitable. Sodiumnitrite has been used most extensively because of its readyavailability.

When the alpha-nitroester sought has no alpha-hydrogen atom, then it isstable to the joint action of the sodium nitrite and the nitrite ester.In such a case the scavenger is not needed, since the alpha-nitroestercan be obtained in good yields without the scavenger, as is illustratedin Example 5. However, if the scavenger is added it will not affect orinterfere with the reaction. If there is an alpha-hydrogen on thealpha-nitroester which is sought, even small amounts of the nitriteester will promote the destruction of large amounts of thealpha-nitroester. In the absence of the scavenger, no alpha-nitroestercan be obtained from bromides and very little from iodides.

Though resorcinol and catechol are operative, they are distinctly lesseflieient then phloroglucinol, and the latter represents by far the mostpreferred embodiment of the invention.

Temperature does not appear to greatly alfect the present process. Inthe preparation of ethyl alpha-nitropropionate equivalent yields wereobtained at 0 and 25 C. At the latter temperature, extension of thereaction time for a considerable period did not result in a lowering ofthe yield. Temperatures as high as 60-70 C., and in some cases even 100C., are operable, though tempera tures below about 40 C. are preferablesince the scavenger functions most efiiciently at the lowertemperatures.

The reaction of the present invention may be represented as follows:

where X is a bromine, iodine, or chlorine atom, R and R are the same ordifferent alkyl, cycloalkyl, aryl, or alkaryl radicals, and M is analkali metal, such as sodium, potassium, or lithium. As can be seen fromthe examples, the alpha-nitroester product in yields of -80% may beobtained.

Alpha-nitroesters prepared by the present invention are useful in a widevariety of organic syntheses, especially in the pharmaceutical field.The nitroesters may be reduced to the aminoesters from which the aminoacids may easily be obtained. Ethyl nitromalonate, which may be preparedfrom ethyl bromomalonate by the process of the present invention, can beused in the preparation of tryptophane, an important alpha-amino acid,according to the method of Lyttle and Weisblett set forth in theAmerican Chemical Society Journal, vol. 69 (Aug-Dec. 1947), pages2118-9.

Having thus described our invention, we intend to be limited only by thefollowing claims.

We claim:

1. A process for preparing an alpha-nitroester having an alpha-hydrogenfrom the corresponding alpha-haloester which comprises mixing thealpha-haloester in dimethylformamide with an alkali metal nitrite and acompound selected from the class consisting of phloroglucinol,resorcinol, and catechol.

2. A process as in claim 1, wherein the last-named compound isphloroglucinol.

3. A process as in claim 1, wherein the alkali metal nitrite is sodiumnitrite.

References Cited in the file of this patent Hickinbottom: Reactions ofOrganic Compounds, pgs. 236 and 237 (1948).

1. A PROCESS FOR PREPARING AN ALPHA- NITROESTER HAVING AN ALPHA-HYDROGENFROM THE CORRESPONDING ALPHA-HALOESTER WHICH COMPRISES MIXING THEALPHA-HALOESTER IN DIMETHYLFORMAMIDE WITH AN ALKALI METAL NITRITE AND ACOMPOUND SELECTED FROM THE CLASS CONSISTING OF PHLOROGLUCINOL,RESORCINOL, AND CATECHOL.